Aporphine and oxoaporphine compounds and pharmaceutical use thereof

Abstract

The invention provides aporphine and oxoaporphine compounds that have endothelial nitric oxide synthase (eNOS) maintaining or enhancing activities and may be used to manufacture a medicaments for preventing or treating ischemic diseases in human and mammal, and the ischemic diseases may include ischemic cerebral apoplexy, ischemic cerebral thrombosis, ischemic cerebral embolism, hypoxic ischemic encephlopathy, ischemic cardiac disease or ischemic enteropathy etc.

Description

[0001] This application claims priority from Taiwanese Application No. TW92107780 filed on Apr. 4, 2003, Chinese Application No. 03137381.X filed on Jun. 19, 2003, and PCT Application No. PCT / CN03 / 00477 filed on Jun. 19, 2003.BACKGROUND OF INVENTION[0002] 1. Field of the Invention[0003] The present invention relates to compounds for treating ischemic diseases, more particularly to aporphine and oxoaporphine compounds that can be used to prevent or treat ischemic diseases based on a mechanism of maintaining or increasing the endothelial nitric oxide synthase (eNOS).[0004] 2. Background of the Invention[0005] With the progress of society and the advance in sciences and technology, life expectancy gradually increases. Many people now suffer from various diseases due to old age, diet, obesity, lack of exercise or living under stress. Among these diseases, ischemic diseases are among the main causes of death and physical impairment. Ischemic diseases have a major impact and cause substan...

AI Technical Summary

Benefits of technology

[0011] Another finding of the present study is that aporphine and oxoaporphine compounds can dilate blood vessels and are more effective in opening up blocked vessels than conventional clot dissolving agents. As compared with MK801, these aporphine and oxoaporphine compounds will not cause memory loss or hypothermic side effects when they are used to treat ischemic diseases. Therefore, these compounds can provide better therapeutic index.

[0029] Compared with the current methods for lysing the infarcted thrombus to open up blood vessels, the compounds of the invention have better therapeutic efficacies by loosening and dilating the blood vessels. There are little side effects in treating the ischemic diseases with the aporphine and oxoaporphine compounds of the invention. These side effects may include, for example, s memory loss, body temperature decreasing.

Problems solved by technology

Ischemic diseases have a major impact and cause substantial loss to people, family, society and the state.

If blood supply cannot be restored in time, nerve cells, glial cells, vascular endothelial cell and smooth muscle cells will die, leading to cerebral infarction and cerebral thrombosis.

However, because patients may suffer cerebral hemorrhagic complication after using a thrombolytic agent, this agent is strictly restricted in its use in a therapeutic window, i.e. "critical period."

Other conventional blood vessel unblocking agents, such as anticoagulants and platelet aggregation inhibitors, can only prevent continued thrombus formation, but cannot lyse the thrombus to re-open occluded blood vessels.

Recent studies show that blood clot dissolving agents can trigger the production and release of oxygen free radicals, platelet activating factor (PAF), and excitotoxic neurotransmitter, such as glutamate, which may act as N-methyl-D-aspartic acid (NMDA) to stimulate the NMDA receptor and consequently lead to neuronal cell death.

These side effects may include, for example, s memory loss, body temperature decreasing.

Because iNOS is calcium-independent and calmodulin-independent, the activity of iNOS once induced cannot be easily terminated and may last for several hours, leading to overproduction of NO, which can be harmful.

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